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Peroxisome Proliferator Activated Receptor Ligands as Regulators of Airway Inflammation and Remodelling in Chronic Lung Disease
Ward, Jane Elizabeth
Tan, Xiahui
PPAR Research
Inflammation is a major component in the pathology of chronic lung diseases, including asthma. Anti-inflammatory treatment with corticosteroids is not effective in all patients. Thus, new therapeutic options are required to control diverse cellular functions that are currently not optimally targeted by these drugs in order to inhibit inflammation and its sequelae in lung disease. Peroxisome proliferator activated receptors (PPARs), originally characterised as regulators of lipid and glucose metabolism, offer marked potential in this respect. PPARs are expressed in both lung infiltrating and resident immune and inflammatory cells, as well as in resident and structural cells in the lungs, and play critical roles in the regulation of airway inflammation. In vitro, endogenous and synthetic ligands for PPARs regulate expression and release of proinflammatory cytokines and chemoattractants, and cell proliferation and survival. In murine models of allergen-induced inflammation, PPARα and PPARγ ligands reduce the influx of inflammatory cells, cytokine and mucus production, collagen deposition, and airways hyperresponsiveness. The activity profiles of PPAR ligands differ to corticosteroids, supporting the hypothesis that PPARs comprise additional therapeutic targets to mimimise the contribution of inflammation to airway remodelling and dysfunction.
Related Articles
Pioglitazone is as effective as dexamethasone in a cockroach allergen-induced murine model of asthma
Narala, Venkata R
Ranga, Rajesh
Smith, Monica R
Berlin, Aaron A
Standiford, Theodore J
Lukacs, Nicholas W
Reddy, Raju C
Respiratory Research
While glucocorticoids are currently the most effective therapy for asthma, associated side effects limit enthusiasm for their use. Peroxisome proliferator-activated receptor-γ (PPAR-γ) activators include the synthetic thiazolidinediones (TZDs) which exhibit anti-inflammatory effects that suggest usefulness in diseases such as asthma. How the ability of TZDs to modulate the asthmatic response compares to that of glucocorticoids remains unclear, however, because these two nuclear receptor agonists have never been studied concurrently. Additionally, effects of PPAR-γ agonists have never been examined in a model involving an allergen commonly associated with human asthma.
We compared the effectiveness of the PPAR-γ agonist pioglitazone (PIO) to the established effectiveness of a glucocorticoid receptor agonist, dexamethasone (DEX), in a murine model of asthma induced by cockroach allergen (CRA). After sensitization to CRA and airway localization by intranasal instillation of the allergen, Balb/c mice were challenged twice at 48-h intervals with intratracheal CRA. Either PIO (25 mg/kg/d), DEX (1 mg/kg/d), or vehicle was administered throughout the period of airway CRA exposure.
PIO and DEX demonstrated similar abilities to reduce airway hyperresponsiveness, pulmonary recruitment of inflammatory cells, serum IgE, and lung levels of IL-4, IL-5, TNF-α, TGF-β, RANTES, eotaxin, MIP3-α, Gob-5, and Muc5-ac. Likewise, intratracheal administration of an adenovirus containing a constitutively active PPAR-γ expression construct blocked CRA induction of Gob-5 and Muc5-ac.
Given the potent effectiveness shown by PIO, we conclude that PPAR-γ agonists deserve investigation as potential therapies for human asthma.
Related Articles
Phytoceramide and sphingoid bases derived from brewer's yeast Saccharomyces pastorianus activate peroxisome proliferator-activated receptors
Murakami, Itsuo
Wakasa, Yukari
Yamashita, Shinji
Kurihara, Toshio
Zama, Kota
Kobayashi, Naoyuki
Mizutani, Yukiko
Mitsutake, Susumu
Shigyo, Tatsuro
Igarashi, Yasuyuki
Lipids in Health and Disease
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that regulate lipid and glucose metabolism. PPARα is highly expressed in the liver and controls genes involved in lipid catabolism. We previously reported that synthetic sphingolipid analogs, part of which contains shorter-length fatty acid chains than natural sphingolipids, stimulated the transcriptional activities of PPARs. Sphingosine and dihydrosphingosine (DHS) are abundant sphingoid bases, and ceramide and dihydroceramide are major ceramide species in mammals. In contrast, phytosphingosine (PHS) and DHS are the main sphingoid bases in fungi. PHS and phytoceramide exist in particular tissues such as the epidermis in mammals, and involvement of ceramide species in PPARβ activation in cultured keratinocytes has been reported. The purpose of the present study is to investigate whether natural sphingolipids with C18 fatty acid and yeast-derived sphingoid bases activate PPARs as PPAR agonists.
Lipids of brewer's yeast contain PHS- and DHS-based sphingolipids. To obtain the sphingoid bases, lipids were extracted from brewer's yeast and acid-hydrolyzed. The sphingoid base fraction was purified and quantified. To assess the effects of sphingolipids on PPAR activation, luciferase reporter assay was carried out. NIH/3T3 and human hepatoma (HepG2) cells were transfected with expression vectors for PPARs and retinoid × receptors, and PPAR responsive element reporter vector. When indicated, the PPAR/Gal4 chimera system was performed to enhance the credibility of experiments. Sphingolipids were added to the cells and the dual luciferase reporter assay was performed to determine the transcriptional activity of PPARs.
We observed that phytoceramide increased the transcriptional activities of PPARs significantly, whereas ceramide and dihydroceramide did not change PPAR activities. Phytoceramide also increased transactivation of PPAR/Gal4 chimera receptors. Yeast-derived sphingoid base fraction, which contained PHS and DHS, or authentic PHS or DHS increased PPAR-dependent transcription. Additionally, phytoceramide stimulated PPARα activity in HepG2 hepatocytes, suggesting that phytoceramide activates genes regulated by PPARα.
Phytoceramide and yeast-derived sphingoid bases activate PPARs, whereas ceramide and dihydroceramide do not change the PPAR activity. The present findings suggest that phytoceramide acts as a PPAR ligand that would regulate PPAR-targeted genes.
PPARs; phytoceramide; brewer's yeast
Related Articles
Balanced pan-PPAR activator bezafibrate in combination with statin: comprehensive lipids control and diabetes prevention?
Tenenbaum, Alexander
Fisman, Enrique Z
Cardiovascular Diabetology
All fibrates are peroxisome proliferators-activated receptors (PPARs)-alpha agonists with ability to decrease triglyceride and increase high density lipoprotein- cholesterol (HDL-C). However, bezafibrate has a unique characteristic profile of action since it activates all three PPAR subtypes (alpha, gamma and delta) at comparable doses. Therefore, bezafibrate operates as a pan-agonist for all three PPAR isoforms. Selective PPAR gamma agonists (thiazolidinediones) are used to treat type 2 diabetes mellitus (T2DM). They improve insulin sensitivity by up-regulating adipogenesis, decreasing free fatty acid levels, and reversing insulin resistance. However, selective PPAR gamma agonists also cause water retention, weight gain, peripheral edema, and congestive heart failure. The expression of PPAR beta/ delta in essentially all cell types and tissues (ubiquitous presence) suggests its potential fundamental role in cellular biology. PPAR beta/ delta effects correlated with enhancement of fatty acid oxidation, energy consumption and adaptive thermogenesis. Together, these data implicate PPAR beta/delta in fuel combustion and suggest that pan-PPAR agonists that include a component of PPAR beta/delta activation might offset some of the weight gain issues seen with selective PPAR gamma agonists, as was demonstrated by bezafibrate studies. Suggestively, on the whole body level all PPARs acting as one orchestra and balanced pan-PPAR activation seems as an especially attractive pharmacological goal. Conceptually, combined PPAR gamma and alpha action can target simultaneously insulin resistance and atherogenic dyslipidemia, whereas PPAR beta/delta properties may prevent the development of overweight. Bezafibrate, as all fibrates, significantly reduced plasma triglycerides and increased HDL-C level (but considerably stronger than other major fibrates). Bezafibrate significantly decreased prevalence of small, dense low density lipoproteins particles, remnants, induced atherosclerotic plaque regression in thoracic and abdominal aorta and improved endothelial function. In addition, bezafibrate has important fibrinogen-related properties and anti-inflammatory effects. In clinical trials bezafibrate was highly effective for cardiovascular risk reduction in patients with metabolic syndrome and atherogenic dyslipidemia. The principal differences between bezafibrate and other fibrates are related to effects on glucose level and insulin resistance. Bezafibrate decreases blood glucose level, HbA1C, insulin resistance and reduces the incidence of T2DM compared to placebo or other fibrates. Currently statins are the cornerstone of the treatment and prevention of cardiovascular diseases related to atherosclerosis. However, despite the increasing use of statins as monotherapy for low density lipoprotein- cholesterol (LDL-C) reduction, a significant residual cardiovascular risk is still presented in patients with atherogenic dyslipidemia and insulin resistance, which is typical for T2DM and metabolic syndrome. Recently, concerns were raised regarding the development of diabetes in statin-treated patients. Combined bezafibrate/statin therapy is more effective in achieving a comprehensive lipid control and residual cardiovascular risk reduction. Based on the beneficial effects of pan-PPAR agonist bezafibrate on glucose metabolism and prevention of new-onset diabetes, one could expect a neutralization of the adverse pro-diabetic effect of statins using the strategy of a combined statin/fibrate therapy.
Atherogenic dyslipidemia; Bezafibrate; Combined fibrate/statin therapy; Metabolic syndrome; PPAR; Prevention; Residual cardiovascular risk; Type 2 diabetes
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Immunoregulatory Actions of Epithelial Cell PPAR γ at the Colonic Mucosa of Mice with Experimental Inflammatory Bowel Disease
Mohapatra, Saroj K.
Guri, Amir J.
Climent, Montse
Vives, Cristina
Carbo, Adria
Horne, William T.
Hontecillas, Raquel
Bassaganya-Riera, Josep
PLoS ONE
Peroxisome proliferator-activated receptors are nuclear receptors highly expressed in intestinal epithelial cells (IEC) and immune cells within the gut mucosa and are implicated in modulating inflammation and immune responses. The objective of this study was to investigate the effect of targeted deletion of PPAR γ in IEC on progression of experimental inflammatory bowel disease (IBD).
Methodology/Principal Findings
In the first phase, PPAR γ flfl; Villin Cre- (VC-) and PPAR γ flfl; Villin Cre+ (VC+) mice in a mixed FVB/C57BL/6 background were challenged with 2.5% dextran sodium sulfate (DSS) in drinking water for 0, 2, or 7 days. VC+ mice express a transgenic recombinase under the control of the Villin-Cre promoter that causes an IEC-specific deletion of PPAR γ. In the second phase, we generated VC- and VC+ mice in a C57BL/6 background that were challenged with 2.5% DSS. Mice were scored on disease severity both clinically and histopathologically. Flow cytometry was used to phenotypically characterize lymphocyte and macrophage populations in blood, spleen and mesenteric lymph nodes. Global gene expression analysis was profiled using Affymetrix microarrays. The IEC-specific deficiency of PPAR γ in mice with a mixed background worsened colonic inflammatory lesions, but had no effect on disease activity (DAI) or weight loss. In contrast, the IEC-specific PPAR γ null mice in C57BL/6 background exhibited more severe inflammatory lesions, DAI and weight loss in comparison to their littermates expressing PPAR γ in IEC. Global gene expression profiling revealed significantly down-regulated expression of lysosomal pathway genes and flow cytometry results demonstrated suppressed production of IL-10 by CD4+ T cells in mesenteric lymph nodes (MLN) of IEC-specific PPAR γ null mice.
Our results demonstrate that adequate expression of PPAR γ in IEC is required for the regulation of mucosal immune responses and prevention of experimental IBD, possibly by modulation of lysosomal and antigen presentation pathways.
Related Articles
Arsenic trioxide, a potent inhibitor of NF-κB, abrogates allergen-induced airway hyperresponsiveness and inflammation
Zhou, Lin-Fu
Zhu, Yi
Cui, Xue-Fan
Xie, Wei-Ping
Hu, Ai-Hua
Yin, Kai-Sheng
Respiratory Research
Overactivation of nuclear factor κB (NF-κB) orchestrates airway eosinophilia, but does not dampen airway hyperresponsiveness in asthma. NF-κB repression by arsenic trioxide (As2O3) contributes to apoptosis of eosinophils (EOS) in airways. Here we provide evidence that As2O3 abrogates allergen (OVA)-induced airway eosinophilia by modulating the expression of IκBα, an NF-κB inhibitory protein, and decreases the airway hyperresponsiveness.
Using a murine model of asthma, the airway hyperresponsiveness was conducted by barometric whole-body plethysmography. Airway eosinophilia, OVA-specific IgE in serum, and chemokine eotaxin and RANTES (regulated upon activation, normal T cell expressed and secreted) in bronchoalveolar lavage fluid were measured by lung histology, Diff-Quick staining, and ELISA. Chemokine-induced EOS chemotactic activity was evaluated using EOS chemotaxis assay. Electrophoretic mobility shift assay and Western blot analysis were performed to assess pulmonary NF-κB activation and IκBα expression, respectively.
As2O3 attenuated the allergen-induced serum IgE, chemokine expression of eotaxin and RANTES, and the EOS recruitment in bronchoalveolar lavage fluid, which is associated with an increased IκBα expression as well as a decreased NF-κB activation. Also, As2O3 suppressed the chemotaxis of EOS dose-dependently in vitro. Additionally, As2O3 significantly ameliorated the allergen-driven airway hyperresponsiveness, the cardinal feature underlying asthma.
These findings demonstrate an essential role of NF-κB in airway eosinophilia, and illustrate a potential dissociation between airway inflammation and hyperresponsiveness. As2O3 likely exerts its broad anti-inflammatory effects by suppression of NF-κB activation through augmentation of IκBα expression in asthma.
Related Articles
Regulation of PPAR gamma gene expression by nutrition and obesity in rodents.
Vidal-Puig, A
Jimenez-Liñan, M
Lowell, B B
Hamann, A
Hu, E
Spiegelman, B
Flier, J S
Moller, D E
Journal of Clinical Investigation
The orphan nuclear receptor, peroxisome proliferator-activated receptor (PPAR) gamma, is implicated in mediating expression of fat-specific genes and in activating the program of adipocyte differentiation. The potential for regulation of PPAR gamma gene expression in vivo is unknown. We cloned a partial mouse PPAR gamma cDNA and developed an RNase protection assay that permits simultaneous quantitation of mRNAs for both gamma l and gamma 2 isoforms encoded by the PPAR gamma gene. Probes for detection of adipocyte P2, the obese gene product, leptin, and 18S mRNAs were also employed. Both gamma l and gamma 2 mRNAs were abundantly expressed in adipose tissue. PPAR gamma 1 expression was also detected at lower levels in liver, spleen, and heart; whereas, gamma l and gamma 2 mRNA were expressed at low levels in skeletal muscle. Adipose tissue levels of gamma l and gamma 2 were not altered in two murine models of obesity (gold thioglucose and ob/ob), but were modestly increased in mice with toxigene-induced brown fat ablation uncoupling protein diphtheria toxin A mice. Fasting (12-48 h) was associated with an 80% fall in PPAR gamma 2 and a 50% fall in PPAR gamma mRNA levels in adipose tissue. Western blot analysis demonstrated a marked effect of fasting to reduce PPAR gamma protein levels in adipose tissue. Similar effects of fasting on PPAR gamma mRNAs were noted in all three models of obesity. Insulin-deficient (streptozotocin) diabetes suppressed adipose tissue gamma l and gamma 2 expression by 75% in normal mice with partial restoration during insulin treatment. Levels of adipose tissue PPAR gamma 2 mRNA were increased by 50% in normal mice exposed to a high fat diet. In obese uncoupling protein diphtheria toxin A mice, high fat feeding resulted in de novo induction of PPAR gamma 2 expression in liver. We conclude (a) PPAR gamma 2 mRNA expression is most abundant in adipocytes in normal mice, but lower level expression is seen in skeletal muscle; (b) expression of adipose tissue gamma1 or gamma2 mRNAs is increased in only one of the three models of obesity; (c) PPAR gamma 1 and gamma 2 expression is downregulated by fasting and insulin-deficient diabetes; and (d) exposure of mice to a high fat diet increases adipose tissue expression of PPAR gamma (in normal mice) and induces PPAR gamma 2 mRNA expression in liver (in obese mice). These findings demonstrate in vivo modulation of PPAR gamma mRNA levels over a fourfold range and provide an additional level of regulation for the control of adipocyte development and function.
Related Articles
Both Hematopoietic-Derived and Non–Hematopoietic-Derived β-Arrestin–2 Regulates Murine Allergic Airway Disease
Hollingsworth, John W.
Theriot, Barbara S.
Li, Zhouwei
Lawson, Barbara L.
Sunday, Mary
Schwartz, David A.
Walker, Julia K. L.
American Journal of Respiratory Cell and Molecular Biology
Allergic asthma, a major cause of morbidity and leading cause of hospitalizations, is an inflammatory disease orchestrated by T helper cells and characterized by the lung migration of eosinophils, which are important asthma effector cells. Lung migration of inflammatory cells requires, among other events, the chemokine receptor transduction of lung-produced inflammatory chemokines. Despite the widespread prevalence of this disease, the molecular mechanisms regulating chemokine production and receptor regulation in asthma are poorly understood. Previous work from our laboratory demonstrated that β-arrestin−2 positively regulates the development of allergic airway disease in a mouse model, partly through positive regulation of T-lymphocyte chemotaxis to the lung. However, β-arrestin−2 is expressed in many cell types, including other hematopoietic cells and lung structural cells, which are involved in the development and manifestation of allergic airway disease. To determine the cell types required for β-arrestin–2–dependent allergic inflammation, we generated bone marrow chimera mice. Using the ovalbumin murine model of allergic airway disease, we show that eosinophilic and lymphocytic inflammation is restored in chimeric mice, with expression of β-arrestin−2 exclusively on hematopoietic-derived cell types. In contrast, airway hyperresponsiveness is dependent on the expression of β-arrestin−2 in structural cells. Our data demonstrate that the expression of β-arrestin−2 in at least two divergent cell types contributes to the pathogenesis of allergic airway disease.
asthma; bone marrow transplant; β-arrestin-2; airway hyperresponsiveness
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PPAR-γ regulates inflammation and renin-angiotensin system activity in hypothalamic paraventricular nucleus and ameliorates peripheral manifestations of heart failure
Yu, Yang
Zhang, Zhi-Hua
Wei, Shun-Guang
Weiss, Robert M
Felder, Robert B
Activation of peroxisome proliferator-activated receptor (PPAR)-γ, a nuclear transcription factor, has been shown to inhibit the production of proinflammatory cytokines and, in peripheral tissues, to down-regulate the renin-angiotensin system (RAS). PPAR-γ is expressed in key brain areas involved in cardiovascular and autonomic regulation. We hypothesized that activation of central PPAR-γ would reduce sympathetic excitation and ameliorate peripheral manifestations of heart failure (HF) by inhibiting central inflammation and brain RAS activity. Two weeks after coronary artery ligation, HF rats received an intracerebroventricular (ICV) infusion of the PPAR-γ agonist pioglitazone or vehicle for another 2 weeks. PPAR- expression in the paraventricular nucleus of hypothalamus (PVN), an important cardiovascular region, was unchanged in HF compared with sham-operated (SHAM) rats. However, PPAR-γ DNA binding activity was reduced, nuclear factor-kB activity was increased, and expression of proinflammatory cytokines and angiotensin II type-1 receptor was augmented in the HF rats. Mean blood pressure response to ganglionic blockade was greater, plasma norepinephrine levels, lung/body weight, right ventricle/body weight, and left ventricular end-diastolic pressure were increased and maximal left ventricular dP/dt was decreased. All these findings were ameliorated in HF rats treated with ICV pioglitazone, which increased PPAR-γ expression and DNA binding activity in PVN. The results demonstrate that cardiovascular and autonomic mechanisms leading to heart failure after myocardial infarction can be modulated by activation of PPAR-γ in the brain. Central PPAR-γ may be a novel target for treatment of sympathetic excitation in myocardial infarction-induced HF.
peroxisome proliferator-activated receptor-γ; proinflammatory cytokines; renin-angiotensin system; nuclear factor-kB; autonomic regulation
Related Articles
Interleukin 12 inhibits antigen-induced airway hyperresponsiveness, inflammation, and Th2 cytokine expression in mice
The Journal of Experimental Medicine
Allergic asthma is characterized by airway hyperresponsiveness and pulmonary eosinophilia, and may be mediated by T helper (Th) lymphocytes expressing a Th2 cytokine pattern. Interleukin (IL) 12 suppresses the expression of Th2 cytokines and their associated responses, including eosinophilia, serum immunoglobulin E, and mucosal mastocytosis. We have previously shown in a murine model that antigen- induced increases in airway hyperresponsiveness and pulmonary eosinophilia are CD4+ T cell dependent. We used this model to determine the ability of IL-12 to prevent antigen-induced increases in airway hyperresponsiveness, bronchoalveolar lavage (BAL) eosinophils, and lung Th2 cytokine expression. Sensitized A/J mice developed airway hyperresponsiveness and increased numbers of BAL eosinophils and other inflammatory cells after single or repeated intratracheal challenges with sheep red blood cell antigen. Pulmonary mRNA and protein levels of the Th2 cytokines IL-4 and IL-5 were increased after antigen challenge. Administration of IL-12 (1 microgram/d x 5 d) at the time of a single antigen challenge abolished the airway hyperresponsiveness and pulmonary eosinophilia and promoted an increase in interferon (IFN) gamma and decreases in IL-4 and IL-5 expression. The effects of IL-12 were partially dependent on IFN-gamma, because concurrent treatment with IL-12 and anti-IFN-gamma monoclonal antibody partially reversed the inhibition of airway hyperresponsiveness and eosinophilia by IL-12. Treatment of mice with IL-12 at the time of a second antigen challenge also prevented airway hyperresponsiveness and significantly reduced numbers of BAL inflammatory cells, reflecting the ability of IL-12 to inhibit responses associated with ongoing antigen-induced pulmonary inflammation. These data show that antigen-induced airway hyperresponsiveness and inflammation can be blocked by IL-12, which suppresses Th2 cytokine expression. Local administration of IL-12 may provide a novel immunotherapy for the treatment of pulmonary allergic disorders such as atopic asthma.
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Hepatocyte Growth Factor Is a Downstream Effector that Mediates the Antifibrotic Action of Peroxisome Proliferator–Activated Receptor-γ Agonists
Li, Yingjian
Wen, Xiaoyan
Spataro, Bradley C.
Hu, Kebin
Dai, Chunsun
Liu, Youhua
Journal of the American Society of Nephrology : JASN
Peroxisome proliferator–activated receptor-γ (PPAR-γ) is a ligand-dependent transcription factor that plays an important role in the regulation of insulin sensitivity and lipid metabolism. Evidence shows that PPAR-γ agonists also ameliorate renal fibrotic lesions in both diabetic nephropathy and nondiabetic chronic kidney disease. However, little is known about the mechanism underlying their antifibrotic action. This study demonstrated that PPAR-γ agonists could exert their actions by inducing antifibrotic hepatocyte growth factor (HGF) expression. Incubation of mesangial cells with natural or synthetic PPAR-γ agonists 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) or troglitazone and ciglitazone suppressed TGF-β1–mediated α-smooth muscle actin, fibronectin, and plasminogen activator inhibitor-1 expression. PPAR-γ agonists also induced HGF mRNA expression and protein secretion. Transfection studies revealed that 15d-PGJ2 stimulated HGF gene promoter activity, which was dependent on the presence of a novel peroxisome proliferator response element. Treatment of mesangial cells with 15d-PGJ2 induced the binding of PPAR-γ to the peroxisome proliferator response element in the HGF promoter region. PPAR-γ agonists also activated c-met receptor tyrosine phosphorylation, induced Smad transcriptional co-repressor TG-interacting factor expression, and blocked TGF-β/Smad-mediated gene transcription in mesangial cells. Furthermore, ablation of c-met receptor through the LoxP-Cre system in mesangial cells abolished the antifibrotic effect of 15d-PGJ2. PPAR-γ activation also induced HGF expression in renal interstitial fibroblasts and repressed TGF-β1–mediated myofibroblast activation. Both HGF and 15d-PGJ2 attenuated Smad nuclear translocation in response to TGF-β1 stimulation in renal fibroblasts. Together, these findings suggest that HGF may act as a downstream effector that mediates the antifibrotic action of PPAR-γ agonists.
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Effects of the PPAR-β agonist GW501516 in an in vitro model of brain inflammation and antibody-induced demyelination
Defaux, Antoinette
Zurich, Marie-Gabrielle
Braissant, Olivier
Honegger, Paul
Monnet-Tschudi, Florianne
Journal of Neuroinflammation
Brain inflammation plays a central role in numerous brain pathologies, including multiple sclerosis (MS). Microglial cells and astrocytes are the effector cells of neuroinflammation. They can be activated also by agents such as interferon-γ (IFN-γ) and lipopolysaccharide (LPS). Peroxisome proliferator-associated receptor (PPAR) pathways are involved in the control of the inflammatory processes, and PPAR-β seems to play an important role in the regulation of central inflammation. In addition, PPAR-β agonists were shown to have trophic effects on oligodendrocytes in vitro, and to confer partial protection in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In the present work, a three-dimensional brain cell culture system was used as in vitro model to study antibody-induced demyelination and inflammatory responses. GW 501516, a specific PPAR-β agonist, was examined for its capacity to protect from antibody-mediated demyelination and to prevent inflammatory responses induced by IFN-γ and LPS.
Aggregating brain cells cultures were prepared from embryonal rat brain, and used to study the inflammatory responses triggered by IFN-γ and LPS and by antibody-mediated demyelination induced by antibodies directed against myelin-oligodendrocyte glycoprotein (MOG). The effects of GW 501516 on cellular responses were characterized by the quantification of the mRNA expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), inducible NO synthase (i-NOS), PPAR-β, PPAR-γ, glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), and high molecular weight neurofilament protein (NF-H). GFAP expression was also examined by immunocytochemistry, and microglial cells were visualized by isolectin B4 (IB4) and ED1 labeling.
GW 501516 decreased the IFN-γ-induced up-regulation of TNF-α and iNOS in accord with the proposed anti-inflammatory effects of this PPAR-β agonist. However, it increased IL-6 m-RNA expression. In demyelinating cultures, reactivity of both microglial cells and astrocytes was observed, while the expression of the inflammatory cytokines and iNOS remained unaffected. Furthermore, GW 501516 did not protect against the demyelination-induced changes in gene expression.
Although GW 501516 showed anti-inflammatory activity, it did not protect against antibody-mediated demyelination. This suggests that the protective effects of PPAR-β agonists observed in vivo can be attributed to their anti-inflammatory properties rather than to a direct protective or trophic effect on oligodendrocytes.
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Potential Relationship between Hepatobiliary Osteopontin and Peroxisome Proliferator–Activated Receptor α Expression following Ethanol-Associated Hepatic Injury In Vivo and In Vitro
Lee, Jin-Hyung
Banerjee, Atrayee
Ueno, Yoshi
Ramaiah, Shashi K.
Toxicological Sciences
Osteopontin (OPN) up-regulation is known to mediate hepatic inflammation in a rodent model of alcoholic liver disease (ALD) and alcohol ingestion is reported to inhibit hepatic peroxisome proliferator–activated receptor-α (PPAR-α) activity leading to hepatic steatosis and inflammation. Therefore, the objective of this study was to investigate the potential relationship between the anti-inflammatory PPAR-α and proinflammatory OPN in rats and mice livers, and cell cultures of hepatocytes and biliary epithelium. Experiments were designed to evaluate the influence of ethanol (EtOH), lipopolysaccharide (LPS), and acetaldehyde (ACA) on OPN and PPAR-α expression levels in vivo (rats and mice) and in vitro (hepatocytes and biliary epithelium). Adult Sprague-Dawley rats and C57BL6 mice were fed EtOH-containing Lieber-DeCarli liquid diet for 6 weeks and injected with a single dose of LPS. A combination of EtOH and LPS treated rats and mice showed significant induction of hepatic OPN expression compared with the controls. Similarly, cells exposed to physiological doses of EtOH, LPS, a combination of EtOH and LPS, and ACA resulted in increased OPN protein and mRNA expression. Rats and mice in ALD model and cells treated with EtOH and ACA showed downregulation of PPAR-α mRNA. Also, DNA binding activity of PPAR-α to PPAR response element was significantly reduced following treatment. Overexpression of PPAR-α rescued the reduced PPAR-α activity and PPAR-α agonist, bezafibrate, elevated PPAR-α activity after treatment of EtOH, LPS, and ACA when cells were exposed by bezafibrate. To further delineate the potential relationship between OPN and PPAR-α, OPN−/− mice showed no change of PPAR-α mRNA level although wild-type mice showed downregulation of PPAR-α mRNA after EtOH treatment. In conclusion, the current study suggests that OPN is induced by EtOH and its metabolite ACA and opposite relationship likely exist between PPAR-α and OPN expression within the liver during ALD.
bezafibrate; ethanol; osteopontin; peroxisome proliferator–activated receptor-α
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Treatment of Allergic Airway Inflammation and Hyperresponsiveness by Antisense-Induced Local Blockade of Gata-3 Expression
Finotto, Susetta
De Sanctis, George T.
Lehr, Hans A.
Herz, Udo
Buerke, Michael
Schipp, Mechthild
Bartsch, Brigitte
Atreya, Raja
Schmitt, Edgar
Galle, Peter R.
Renz, Harald
Neurath, Markus F.
The Journal of Experimental Medicine
Recent studies in transgenic mice have revealed that expression of a dominant negative form of the transcription factor GATA-3 in T cells can prevent T helper cell type 2 (Th2)-mediated allergic airway inflammation in mice. However, it remains unclear whether GATA-3 plays a role in the effector phase of allergic airway inflammation and whether antagonizing the expression and/or function of GATA-3 can be used for the therapy of allergic airway inflammation and hyperresponsiveness. Here, we analyzed the effects of locally antagonizing GATA-3 function in a murine model of asthma. We could suppress GATA-3 expression in interleukin (IL)-4–producing T cells in vitro and in vivo by an antisense phosphorothioate oligonucleotide overlapping the translation start site of GATA-3, whereas nonsense control oligonucleotides were virtually inactive. In a murine model of asthma associated with allergic pulmonary inflammation and hyperresponsiveness in ovalbumin (OVA)-sensitized mice, local intranasal administration of fluorescein isothiocyanate–labeled GATA-3 antisense oligonucleotides led to DNA uptake in lung cells associated with a reduction of intracellular GATA-3 expression. Such intrapulmonary blockade of GATA-3 expression caused an abrogation of signs of lung inflammation including infiltration of eosinophils and Th2 cytokine production. Furthermore, treatment with antisense but not nonsense oligonucleotides induced a significant reduction of airway hyperresponsiveness in OVA-sensitized mice to levels comparable to saline-treated control mice, as assessed by both enhanced pause (PenH) responses and pulmonary resistance determined by body plethysmography. These data indicate a critical role for GATA-3 in the effector phase of a murine asthma model and suggest that local delivery of GATA-3 antisense oligonucleotides may be a novel approach for the treatment of airway hyperresponsiveness such as in asthma. This approach has the potential advantage of suppressing the expression of various proinflammatory Th2 cytokines simultaneously rather than suppressing the activity of a single cytokine.
GATA-3; antisense DNA; asthma; T cells; Th2 cytokines
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Antigen-sensitized CD4+CD62Llow memory/effector T helper 2 cells can induce airway hyperresponsiveness in an antigen free setting
Nakagome, Kazuyuki
Dohi, Makoto
Okunishi, Katsuhide
To, Yasuo
Sato, Atsushi
Komagata, Yoshinori
Nagatani, Katsuya
Tanaka, Ryoichi
Yamamoto, Kazuhiko
Respiratory Research
Airway hyperresponsiveness (AHR) is one of the most prominent features of asthma, however, precise mechanisms for its induction have not been fully elucidated. We previously reported that systemic antigen sensitization alone directly induces AHR before development of eosinophilic airway inflammation in a mouse model of allergic airway inflammation, which suggests a critical role of antigen-specific systemic immune response itself in the induction of AHR. In the present study, we examined this possibility by cell transfer experiment, and then analyzed which cell source was essential for this process.
BALB/c mice were immunized with ovalbumin (OVA) twice. Spleen cells were obtained from the mice and were transferred in naive mice. Four days later, AHR was assessed. We carried out bronchoalveolar lavage (BAL) to analyze inflammation and cytokine production in the lung. Fluorescence and immunohistochemical studies were performed to identify T cells recruiting and proliferating in the lung or in the gut of the recipient. To determine the essential phenotype, spleen cells were column purified by antibody-coated microbeads with negative or positive selection, and transferred. Then, AHR was assessed.
Transfer of spleen cells obtained from OVA-sensitized mice induced a moderate, but significant, AHR without airway antigen challenge in naive mice without airway eosinophilia. Immunization with T helper (Th) 1 elicited antigen (OVA with complete Freund's adjuvant) did not induce the AHR. Transferred cells distributed among organs, and the cells proliferated in an antigen free setting for at least three days in the lung. This transfer-induced AHR persisted for one week. Interleukin-4 and 5 in the BAL fluid increased in the transferred mice. Immunoglobulin E was not involved in this transfer-induced AHR. Transfer of in vitro polarized CD4+ Th2 cells, but not Th1 cells, induced AHR. We finally clarified that CD4+CD62Llow memory/effector T cells recruited in the lung and proliferated, thus induced AHR.
These results suggest that antigen-sensitized memory/effector Th2 cells themselves play an important role for induction of basal AHR in an antigen free, eosinophil-independent setting. Therefore, regulation of CD4+ T cell-mediated immune response itself could be a critical therapeutic target for allergic asthma.
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Activation of peroxisome proliferator-activated receptors by chlorinated hydrocarbons and endogenous steroids.
Zhou, Y C
Waxman, D J
Environmental Health Perspectives
1998;106(Suppl 4):983-988.
Trichloroethylene (TCE) and related hydrocarbons constitute an important class of environmental pollutants whose adverse effects on liver, kidney, and other tissues may, in part, be mediated by peroxisome proliferator-activated receptors (PPARs), ligand-activated transcription factors belonging to the steroid receptor superfamily. Activation of PPAR induces a dramatic proliferation of peroxisomes in rodent hepatocytes and ultimately leads to hepatocellular carcinoma. To elucidate the role of PPAR in the pathophysiologic effects of TCE and its metabolites, it is important to understand the mechanisms whereby PPAR is activated both by TCE and endogenous peroxisome proliferators. The investigations summarized in this article a) help clarify the mechanism by which TCE and its metabolites induce peroxisome proliferation and b) explore the potential role of the adrenal steroid and anticarcinogen dehydroepiandrosterone 3beta-sulfate (DHEA-S) as an endogenous PPAR activator. Transient transfection studies have demonstrated that the TCE metabolites trichloroacetate and dichloroacetate both activate PPAR alpha, a major liver-expressed receptor isoform. TCE itself was inactive when tested over the same concentration range, suggesting that its acidic metabolites mediate the peroxisome proliferative potential of TCE. Although DHEA-S is an active peroxisome proliferator in vivo, this steroid does not stimulate trans-activation of PPAR alpha or of two other PPAR isoforms, gamma and delta/Nuc1, when evaluated in COS-1 cell transfection studies. To test whether PPAR alpha mediates peroxisomal gene induction by DHEA-S in intact animals, DHEA-S has been administered to mice lacking a functional PPAR alpha gene. DHEA-S was thus shown to markedly increase hepatic expression of two microsomal P4504A proteins associated with the peroxisomal proliferative response in wild-type mice. In contrast, DHEA-S did not induce these hepatic proteins in PPAR alpha-deficient mice. Thus, despite its unresponsiveness to steroidal peroxisome proliferators in transfection assays, PPAR alpha is an obligatory mediator of DHEA-S-stimulated hepatic peroxisomal gene induction. DHEA-S, or one of its metabolites, may thus serve as an important endogenous regulator of liver peroxisomal enzyme expression.
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Oxidative metabolism of linoleic acid modulates PPAR-beta/delta suppression of PPAR-gamma activity
Zuo, Xiangsheng
Wu, Yuanqing
Morris, Jeffrey S.
Stimmel, Julie B.
Leesnitzer, Lisa M.
Fischer, Susan M.
Lippman, Scott M.
Shureiqi, Imad
Peroxisome proliferator–activated receptors (PPARs) are transcription factors that strongly influence molecular events in normal and cancer cells. PPAR-beta/delta overexpression suppresses the activity of PPAR-gamma and -alpha. This interaction has been questioned, however, by studies with synthetic ligands of PPARs in PPAR-beta/delta–null cells, and it is not known whether an interaction between PPAR-beta/delta and -gamma exists, especially in relation to the signaling by natural PPAR ligands. Oxidative metabolites of linoleic and arachidonic acids are natural ligands of PPARs. 13-S-hydroxyoctadecadienoic acid (13-S-HODE), the main product of 15-lipoxygenase-1 (15-LOX-1) metabolism of linoleic acid, downregulates PPAR-beta/delta. We tested (a) whether PPAR-beta/delta expression modulates PPAR-gamma activity in experimental models of the loss and gain of PPAR-beta/delta function in colon cancer cells and (b) whether 15-LOX-1 formation of 13-S-HODE influences the interaction between PPAR-beta/delta and PPAR-gamma. We found that (a) 15-LOX-1 formation of 13-S-HODE promoted PPAR-gamma activity, (b) PPAR-beta/delta expression suppressed PPAR-gamma activity in models of both loss and gain of PPAR-beta/delta function, (c) 15-LOX-1 activated PPAR-gamma by downregulating PPAR-beta/delta , and (d) 15-LOX-1 expression induced apoptosis in colon cancer cells via modulating PPAR-beta/delta suppression of PPAR-gamma. These findings elucidate a novel mechanism of the signaling by natural ligands of PPARs, which involves modulating the interaction between PPAR-beta/delta and PPAR-gamma.
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Effect of NDP-α-MSH on PPAR-γ and –β Expression and Anti-Inflammatory Cytokine Release in Rat Astrocytes and Microglia
Carniglia, Lila
Durand, Daniela
Caruso, Carla
Lasaga, Mercedes
PLoS ONE
Brain inflammation plays a central role in numerous brain pathologies. Microglia and astrocytes are the main effector cells that become activated when an inflammatory process takes place within the central nervous system. α-melanocyte-stimulating hormone (α-MSH) is a neuropeptide with proven anti-inflammatory properties. It binds with highest affinity to the melanocortin receptor 4 (MC4R), which is present in astrocytes and upon activation triggers anti-inflammatory pathways. The aim of this research was to identify anti-inflammatory mediators that may participate in the immunomodulatory effects of melanocortins in glial cells. Since peroxisome proliferator-activated receptors (PPARs) have recently been implicated in the modulation of inflammation, we investigated the effect of an α-MSH analog, [Nle4, D-Phe7]-α-MSH (NDP-α-MSH), on PPAR-β and PPAR-γ gene and protein expression in rat primary astrocytes and microglia. We initially demonstrated that rat primary microglia express MC4R and showed that treatment with NDP-α-MSH increases PPAR-γ protein levels and strongly decreases PPAR-β levels in both astrocytes and microglia. We also showed that extracellular signal-regulated kinase 1/2 (ERK1/2)–mediated signaling is partially involved in these effects in a cell-specific fashion. Finally, we showed that NDP-α-MSH stimulates the release of the anti-inflammatory cytokines IL-10 and TGF-β from microglia and astrocytes, respectively. The presented data suggest a role for IL-10 and TGF-β in the protective action of melanocortins and a connection between MC4R pathway and that of the nuclear receptor PPAR-γ. This is the first report providing evidence that MC4R is expressed in rat primary microglia and that melanocortins modulate PPAR levels in glial cells. Our findings provide new insights into the mechanisms underlying the activation of glial MC4R and open perspectives for new therapeutic strategies for the treatment of inflammation-mediated brain diseases.
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Peroxisome Proliferator-Activated Receptor-Gamma Expression in the Lung Tissue of Obese Rats
Hwang, Su Jin
Kim, Jung Ho
Shim, Jae Won
Kim, Duk Soo
Jung, Hye Lim
Park, Moon Soo
Lee, Won Young
Kim, Se-Yeon
Shim, Jung Yeon
Yonsei Medical Journal
Obesity is a risk factor for asthma and type II diabetes. Peroxisome proliferator-activated receptor (PPAR)-γ has been suggested to regulate inflammatory responses in diabetes and asthma. We investigated whether PPAR-α, PPAR-γ, adiponectin receptors (AdipoR1, AdipoR2), leptin, and tumor necrosis factor (TNF)-α are expressed in rat lung tissues and whether the expression differs between obese Otsuka Long-Evans Tokushima Fatty (OLETF) and lean Long Evans Tokushima Otsuka (LETO) rats.
Materials and Methods
Obese and lean rats were given with a high fat diet or a 30% restricted diet for 32 weeks, and their blood glucose levels and weights were monitored. After 32 weeks, mRNA levels of PPAR-α, PPAR-γ, AdipoR1, AdipoR2, leptin, and TNF-α in lung tissues were measured using real time PCR.
PPAR-α, PPAR-γ, AdipoR1, AdipoR2, leptin, and TNF-α were expressed in both obese and lean rat lung tissues. Increased serum glucose levels on intraperitoneal glucose tolerance testing and a higher weight gain at 32 weeks were observed in OLETF control rats compared to OLETF diet restricted rats. PPAR-γ expression was markedly elevated in obese control and diet restricted rats compared to lean rats, although PPAR-γ expression in obese rats was not affected by diet restriction. Leptin was highly expressed in OLETF rats compared to LETO rats. TNF-α expression was enhanced in OLETF control rats compared LETO diet restricted rats, and decreased by diet restriction. PPAR-α, AdipoR1, and AdipoR2 expression were not significantly different between obese and lean rats.
PPAR-γ was highly expressed in the lung tissues of obese rats and may be a novel treatment target for regulating lung inflammation associated with obesity.
Obesity; peroxisome proliferator activated receptor; adiponectin receptor; lung; leptin; TNF-alpha
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Peroxisome Proliferator-Activated Receptor Targets for the Treatment of Metabolic Diseases
Monsalve, Francisco A.
Pyarasani, Radha D.
Delgado-Lopez, Fernando
Moore-Carrasco, Rodrigo
Mediators of Inflammation
Metabolic syndrome is estimated to affect more than one in five adults, and its prevalence is growing in the adult and pediatric populations. The most widely recognized metabolic risk factors are atherogenic dyslipidemia, elevated blood pressure, and elevated plasma glucose. Individuals with these characteristics commonly manifest a prothrombotic state and a proinflammatory state as well. Peroxisome proliferator-activated receptors (PPARs) may serve as potential therapeutic targets for treating the metabolic syndrome and its related risk factors. The PPARs are transcriptional factors belonging to the ligand-activated nuclear receptor superfamily. So far, three isoforms of PPARs have been identified, namely, PPAR-α, PPAR-β/δ, and PPAR-γ. Various endogenous and exogenous ligands of PPARs have been identified. PPAR-α and PPAR-γ are mainly involved in regulating lipid metabolism, insulin sensitivity, and glucose homeostasis, and their agonists are used in the treatment of hyperlipidemia and T2DM. Whereas PPAR-β/δ function is to regulate lipid metabolism, glucose homeostasis, anti-inflammation, and fatty acid oxidation and its agonists are used in the treatment of metabolic syndrome and cardiovascular diseases. This review mainly focuses on the biological role of PPARs in gene regulation and metabolic diseases, with particular focus on the therapeutic potential of PPAR modulators in the treatment of thrombosis.
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ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-α and PGC-1
Haemmerle, Guenter
Moustafa, Tarek
Woelkart, Gerald
Büttner, Sabrina
Schmidt, Albrecht
van de Weijer, Tineke
Hesselink, Matthijs
Jaeger, Doris
Kienesberger, Petra C
Zierler, Kathrin
Schreiber, Renate
Eichmann, Thomas
Kolb, Dagmar
Kotzbeck, Petra
Schweiger, Martina
Kumari, Manju
Eder, Sandra
Schoiswohl, Gabriele
Wongsiriroj, Nuttaporn
Pollak, Nina M
Radner, Franz P W
Preiss-Landl, Karina
Kolbe, Thomas
Rülicke, Thomas
Pieske, Burkert
Trauner, Michael
Lass, Achim
Zimmermann, Robert
Hoefler, Gerald
Cinti, Saverio
Kershaw, Erin E
Schrauwen, Patrick
Madeo, Frank
Mayer, Bernd
Zechner, Rudolf
Nature medicine
Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate genes involved in energy metabolism and inflammation. For biological activity, PPARs require cognate lipid ligands, heterodimerization with retinoic × receptors, and coactivation by PPAR-γ coactivator-1α or PPAR-γ coactivator-1β (PGC-1α or PGC-1β, encoded by Ppargc1a and Ppargc1b, respectively). Here we show that lipolysis of cellular triglycerides by adipose triglyceride lipase (patatin-like phospholipase domain containing protein 2, encoded by Pnpla2; hereafter referred to as Atgl) generates essential mediator(s) involved in the generation of lipid ligands for PPAR activation. Atgl deficiency in mice decreases mRNA levels of PPAR-α and PPAR-δ target genes. In the heart, this leads to decreased PGC-1α and PGC-1β expression and severely disrupted mitochondrial substrate oxidation and respiration; this is followed by excessive lipid accumulation, cardiac insufficiency and lethal cardiomyopathy. Reconstituting normal PPAR target gene expression by pharmacological treatment of Atgl-deficient mice with PPAR-α agonists completely reverses the mitochondrial defects, restores normal heart function and prevents premature death. These findings reveal a potential treatment for the excessive cardiac lipid accumulation and often-lethal cardiomyopathy in people with neutral lipid storage disease, a disease marked by reduced or absent ATGL activity.
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Mathew, Anuja
MacLean, James A.
DeHaan, Elliot
Tager, Andrew M.
Green, Francis H.Y.
Luster, Andrew D.
The Journal of Experimental Medicine
Antigen-specific CD4 T helper type 2 (Th2) cells play a pivotal role in the induction of allergic asthma, but the mechanisms regulating their recruitment into the airways are unknown. Signal transducer and activator of transcription factor (Stat)6 is a transcription factor essential for Th2 cell differentiation. Here we show that Stat6 also controls Th2 cell recruitment and effector function in allergic inflammation in vivo. To isolate the role of Stat6 in regulating Th2 cell trafficking and effector function from its role in Th2 cell differentiation, we used a murine model of asthma in which in vitro–differentiated Stat6+/+ antigen-specific Th2 cells were adoptively transferred into naive Stat6−/− and Stat6+/+ mice followed by aerosol antigen challenge. We found that all of the features of asthma, including Th2 cell accumulation, Th2 and eosinophil-active chemokine production, and airway eosinophilia, mucus production, and hyperresponsiveness seen in Stat6+/+ mice, were dramatically absent in Stat6−/− mice that received Stat6+/+ antigen-specific Th2 cells. Our findings establish Stat6 as essential for Th2 cell trafficking and effector function and suggest that interruption of Stat6 signaling in resident cells of the lung is a novel approach to asthma therapy.
asthma; cytokines; eosinophil; transcription factor; knockout mouse
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PPARγ Downregulation by TGFß in Fibroblast and Impaired Expression and Function in Systemic Sclerosis: A Novel Mechanism for Progressive Fibrogenesis
Wei, Jun
Ghosh, Asish K.
Sargent, Jennifer L.
Komura, Kazuhiro
Wu, Minghua
Huang, Qi-Quan
Jain, Manu
Whitfield, Michael L.
Feghali-Bostwick, Carol
Varga, John
PLoS ONE
The nuclear orphan receptor peroxisome proliferator-activated receptor-gamma (PPAR-γ) is expressed in multiple cell types in addition to adipocytes. Upon its activation by natural ligands such as fatty acids and eicosanoids, or by synthetic agonists such as rosiglitazone, PPAR-γ regulates adipogenesis, glucose uptake and inflammatory responses. Recent studies establish a novel role for PPAR-γ signaling as an endogenous mechanism for regulating transforming growth factor-ß (TGF-ß)-dependent fibrogenesis. Here, we sought to characterize PPAR-γ function in the prototypic fibrosing disorder systemic sclerosis (SSc), and delineate the factors governing PPAR-γ expression. We report that PPAR-γ levels were markedly diminished in skin and lung biopsies from patients with SSc, and in fibroblasts explanted from the lesional skin. In normal fibroblasts, treatment with TGF-ß resulted in a time- and dose-dependent down-regulation of PPAR-γ expression. Inhibition occurred at the transcriptional level and was mediated via canonical Smad signal transduction. Genome-wide expression profiling of SSc skin biopsies revealed a marked attenuation of PPAR-γ levels and transcriptional activity in a subset of patients with diffuse cutaneous SSc, which was correlated with the presence of a "TGF-ß responsive gene signature" in these biopsies. Together, these results demonstrate that the expression and function of PPAR-γ are impaired in SSc, and reveal the existence of a reciprocal inhibitory cross-talk between TGF-ß activation and PPAR-γ signaling in the context of fibrogenesis. In light of the potent anti-fibrotic effects attributed to PPAR-γ, these observations lead us to propose that excessive TGF-ß activity in SSc accounts for impaired PPAR-γ function, which in turn contributes to unchecked fibroblast activation and progressive fibrosis.
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Anti-inflammatory properties of a dual PPARgamma/alpha agonist muraglitazar in in vitro and in vivo models
Paukkeri, Erja-Leena
Leppänen, Tiina
Lindholm, Mira
Yam, Mun Fei
Asmawi, Mohd Zaini
Kolmonen, Anne
Aulaskari, Paula H
Moilanen, Eeva
Arthritis Research & Therapy
Peroxisome proliferator-activated receptor (PPAR) agonists are widely used drugs in the treatment of diabetes and dyslipidemia. In addition to their metabolic effects, PPAR isoforms PPARα and PPARγ are also involved in the regulation of immune responses and inflammation. In the present study, we investigated the effects of a dual PPARγ/α agonist muraglitazar on inflammatory gene expression in activated macrophages and on carrageenan-induced inflammation in the mouse.
J774 murine macrophages were activated by lipopolysaccharide (LPS) and treated with dual PPARγ/α agonist muraglitazar, PPARγ agonist GW1929 or PPARα agonist fenofibrate. The effects of PPAR agonists on cytokine production and the activation of inducible nitric oxide synthase (iNOS) pathway were investigated by ELISA, Griess method, Western blotting and quantitative RT-PCR. Nuclear translocation, DNA-binding activity and reporter gene assays were used to assess the activity of nuclear factor kappa B (NF-kB) transcription factor. Carrageenan-induced paw oedema was used as an in vivo model of acute inflammation.
Muraglitazar as well as PPARγ agonist GW1929 and PPARα agonist fenofibrate inhibited LPS-induced iNOS expression and NO production in activated macrophages in a dose-dependent manner. Inhibition of iNOS expression by muraglitazar included both transcriptional and post-transcriptional components; the former being shared by GW1929 and the latter by fenofibrate. All tested PPAR agonists also inhibited IL-6 production, while TNFα production was reduced by muraglitazar and GW1929, but not by fenofibrate. Interestingly, the anti-inflammatory properties of muraglitazar were also translated in vivo. This was evidenced by the finding that muraglitazar inhibited carrageenan-induced paw inflammation in a dose-dependent manner in mice as did iNOS inhibitor L-NIL and anti-inflammatory steroid dexamethasone.
These results show that muraglitazar has anti-inflammatory properties both in vitro and in vivo and these effects reflect the agonistic action through both PPARα and PPARγ.
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Peroxisome proliferator-activated receptor gene expression in human tissues. Effects of obesity, weight loss, and regulation by insulin and glucocorticoids.
Vidal-Puig, A J
Considine, R V
Jimenez-Liñan, M
Werman, A
Pories, W J
Caro, J F
Flier, J S
Journal of Clinical Investigation
The peroxisome proliferator activated receptor (PPAR gamma) plays a key role in adipogenesis and adipocyte gene expression and is the receptor for the thiazolidinedione class of insulin-sensitizing drugs. The tissue expression and potential for regulation of human PPAR gamma gene expression in vivo are unknown. We have cloned a partial human PPAR gamma cDNA, and established an RNase protection assay that permits simultaneous measurements of both PPAR gamma1 and PPAR gamma2 splice variants. Both gamma1 and gamma2 mRNAs were abundantly expressed in adipose tissue. PPAR gamma1 was detected at lower levels in liver and heart, whereas both gamma1 and gamma2 mRNAs were expressed at low levels in skeletal muscle. To examine the hypothesis that obesity is associated with abnormal adipose tissue expression of PPAR gamma, we quantitated PPARgamma mRNA splice variants in subcutaneous adipose tissue of 14 lean and 24 obese subjects. Adipose expression of PPARgamma 2 mRNA was increased in human obesity (14.25 attomol PPAR gamma2/18S in obese females vs 9.9 in lean, P = 0.003). This increase was observed in both male and females. In contrast, no differences were observed in PPAR gamma1/18S mRNA expression. There was a strong positive correlation (r = 0.70, P < 0.001) between the ratio of PPAR gamma2/gamma1 and the body mass index of these patients. We also observed sexually dimorphic expression with increased expression of both PPAR gamma1 and PPAR gamma2 mRNAs in the subcutaneous adipose tissue of women compared with men. To determine the effect of weight loss on PPAR gamma mRNA expression, seven additional obese subjects were fed a low calorie diet (800 Kcal) until 10% weight loss was achieved. Mean expression of adipose PPAR gamma2 mRNA fell 25% (P = 0.0250 after a 10% reduction in body weight), but then increased to pretreatment levels after 4 wk of weight maintenance. Nutritional regulation of PPAR gamma1 was not seen. In vitro experiments revealed a synergistic effect of insulin and corticosteroids to induce PPAR gamma expression in isolated human adipocytes in culture. We conclude that: (a) human PPAR gamma mRNA expression is most abundant in adipose tissue, but lower level expression of both splice variants is seen in skeletal muscle; to an extent that is unlikely to be due to adipose contamination. (b) RNA derived from adipose tissue of obese humans has increased expression of PPAR gamma 2 mRNA, as well as an increased ratio of PPAR gamma2/gamma1 splice variants that is proportional to the BMI; (c) a low calorie diet specifically down-regulates the expression of PPAR gamma2 mRNA in adipose tissue of obese humans; (d) insulin and corticosteroids synergistically induce PPAR gamma mRNA after in vitro exposure to isolated human adipocytes; and (e) the in vivo modulation of PPAR gamma2 mRNA levels is an additional level of regulation for the control of adipocyte development and function, and could provide a molecular mechanism for alterations in adipocyte number and function in obesity.
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Khartoum was a champion racehorse owned by movie producer Jack Woltz.
The Triple-Crown winner was bought for $600,000 by Woltz and who put his horse out to "stud". The horse had a fine stable built for him, the best vets and horse breeders that money could buy, and even a small team of private detectives to guard him 'round the clock. Woltz was very attached to the horse, his pride and affection for the animal clearly evident. Khartoum was eventually killed and decapitated and then put in Woltz's bed by Luca Brasi to convince Woltz to grant Johnny Fontane the lead in the new war movie he was shooting. Upon discovering Khartoum's severed head, Woltz swore his staff to secrecy and had Khartoum quietly buried and his stables all torn down.
- Khartoum is a reference to Charles Gordon, the British commander of Khartoum in the Sudan in 1885, who was captured by Sudanese and was ironically also beheaded.[1]Cite error: Closing </ref> missing for <ref> tag.
Video gameEdit
In The Godfather Game, Aldo Trapani and Rocco Lampone are tasked with delivering the horse head to Woltz's bed. Aldo watches out for guards while Rocco kills the horse and its panicked neighing can be heard. Aldo then escorts Rocco into Woltz's mansion avoiding his servants and guards and plants it in Woltz's bed.
Notes and referencesEdit
- ↑ Lebo, Harlan (2005). The Godfather Legacy. Fireside. ISBN 0743287770.


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Despite recommendations from two judges that TXU Corp. be denied permits to build two coal-fired power plants in Texas due to environmental concerns, environmental regulators in the state have granted the firm permission for the plants. State hearing officers warned that pollution control equipment may not work as promised, but the Texas Commission on Environmental Quality approved an air permit for the two 800-megawatt units.
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A 3-D carbon nanotube mesh enables rat spinal tissue sections to reconnect in culture.
Ernst Haeckel's Pedigree of Man, 1874
August 1, 2011|
After completing his studies in medicine and biology, a restless Ernst Haeckel set off for Italy in 1859 to study art and marine biology. The diversity of life fascinated the 26-year-old Prussian, and in addition to painting landscapes, he spent the


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April 05, 2010
From Ghana to Ukraine, countries around the world saw their cities devolve into pillow-swinging madness on April 3 as International Pillow Fight Day gripped their citizens. Here in Atlanta, several dozen fighters reveled in feathery fun at Freedom Park, while almost as many photographers captured the flight of the pillows.
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Book your room at Rumi Apartelle Hotel
Get an overview of this hotelSuburban Angeles City hotel in Malabanias with free local shuttle
Located in Malabanias, this hotel is within 1 mi (2 km) of Bayanihan Park, Salakot Arch, and Walking Street. SM City Clark and Casino Filipino are also within 2 mi (3 km).
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All 21 rooms offer free WiFi, 24-hour room service, and LCD TVs with cable channels. Phones and desks are also available to guests.Would you like to give us feedback? Share it! Opens in a new window
Rumi Apartelle Hotel339 Sierra Madre Street Perimeter Road Don Juico Avenue Angeles City Pampanga 2009
Hotel Amenities
Hotel Amenities
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Senate legislation could increase illegal immigration
Published: Thursday, March 30, 2006 at 3:15 a.m.
Last Modified: Thursday, March 30, 2006 at 12:00 a.m.
A Senate committee passed a guest worker bill this week that could start a new wave of illegal immigration unless lawmakers do more to improve border security.
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Senators say the bill is not amnesty because it would take undocumented aliens 11 years to achieve citizenship. They would have to pay a fine, pay back taxes, undergo a background check and learn English to earn their citizenship.
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Without tighter border security improvements, the Senate bill is an incentive package for future illegal immigrants.
This story appeared in print on page A10
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